High plasma lipids and lipoproteins are risk factors for various cardiovascular and metabolic disorders. Statins enhance the removal of apolipoprotein B (apoB)-lipoproteins and lower plasma cholesterol. Another approach to lower plasma lipids is to inhibit the biosynthesis of apoB-lipoproteins, a process critically dependent on an endoplasmic reticulum (ER) resident chaperone, microsomal triglyceride transfer protein (MTP). MTP inhibitors decrease apoB-lipoprotein secretion and lower plasma cholesterol. However, they increase plasma aminotransferases, such as ALT and AST, indicating liver injury. Therefore, what is needed is an improved method for treating high plasma lipids and lipoproteins increases in microsomal free cholesterol, without causing an increase in induction of Endoplasmic Reticulum stress and cell death.
An estimated 35.4 million Americans in the United States aged 20 or over have total blood cholesterol levels of >240 mg/dl (normal <200 mg/dl). Hyperlipidemic states (total blood cholesterol >200 mg/dl; LDL Cholesterol >100 mg/dl) have been implicated as a major risk factor for cardiovascular disease (CVD), the leading cause of death in the United States for the past 80 years. Numerous clinical trials and outcome studies have demonstrated that improving such dyslipidemia lowers the progression of atherosclerosis as well as the resulting adverse cardiovascular (CV) events. Statins that remove apolipoprotein B (apoB)-containing lipoproteins from plasma have long been the cornerstone of lowering plasma cholesterol.
Despite their acclaim as the “miracle drug”, approximately 60% of statin-treated patients continue to have adverse coronary events. Furthermore, many patients cannot achieve current target levels for cholesterol owing either to intolerance or an inadequate response to conventional statin therapy. Increasing dosage of statins to try and reach target levels result in an increased likelihood of encountering statin related side effects such as, rhabdomyolysis. Therefore, there is a need to formulate new approaches or regimens to treat hyperlipidemia. One possible approach is to lower plasma lipids at the stage of lipoprotein biosynthesis. Lipoprotein biosynthesis depends on the carrier protein, apolipoprotein B (apoB), and the chaperone, microsomal triglyceride transfer protein (MTP). MTP transfers triglycerides, phospholipids and cholesterol esters to nascent apoB, which readies the protein for secretion as either a chylomicron from the intestine or as VLDL from the liver.
The present invention is directed to a therapeutic combination and a method for lowering the high plasma lipids and lipoproteins in the blood of a patient without the negative effects of many of the existing drugs/procedures available on the market today.